The goal of the present studies is to elucidate the macromolecular structure of chromatin at its various levels of organization. A number of specific approaches are being tried. Employing bifunctional chemicals (e.g., glutaraldehyde and bis imidoesters), nuclear proteins in close proximity are cross-linked, isolated and characterized. Specifically, we have observed that fixation of chicken erythrocyte nuclei by low concentrations of glutaraldehyde (4 mM) very rapidly leads to the formation of cross-linked polymers, principally composed of one histone-type, F2C. A different approach, employed in our laboratory, is directed at a visualization of chromatin ultrastructure by electron microscopy, with attempts to correlate this data to low-angle X-ray diffraction studies. The EM studies have led to a striking finding. Isolated nuclei, swollen in water, centrifuged onto microscope grids and negatively stained reveal spherical "particles-on-a-string." These bodies, denoted upsilon have an average diameter of approximately 70 angstrom units. Approximate calculations suggest that each particle could contain 375-750 angstrom units of double-stranded DNA and 1-2 of each of the five histone types. We propose to continue both of these directions of studies, exploring whether close packing of the spheroid upsilon bodies could account for the X-ray data, and attempting to relate histone- histone proximities to the internal structure and association of these chromatin particles.